MRSA

Overview of Methicillin-resistant Staphylococcus aureus (MRSA)

Part 1

By Jimmy D. Bartlett, OD, DOS, ScD and Chris Snyder, OD, MS, FAAO

Infection by methicillin-resistant Staphylococcus aureus (MRSA) is a growing concern that presents implications for both systemic and ophthalmic health. Eyecare and healthcare providers should be familiar with the clinical characteristics of a MRSA infection and with the treatment and management protocols for MRSA. They should be familiar with infection prevention control measures for clinical practice and they should know how to decrease the potential for MRSA infection in their patients through appropriate recommendations and counseling.

Staphylococcus aureus, often referred to simply as "staph," is a common bacterium that's colonized on human skin and in the noses of 25% to 30% of the population of healthy people.1 It can affect individuals of any age. Individuals are said to be "colonized" when bacteria are present, but not harming the host or causing symptoms.1,2 Staph is the most common cause of localized skin infections, such as folliculitis, furuncles (boils), pimples and impetigo. Moreover, the endo- and exotoxins from staph on the eyelids can cause inflammatory conditions such as staphylococcal blepharitis, phlyctenular conjunctivitis and infiltrative keratitis. Staph can be a serious pathogen, particularly when associated with a wound to the skin, surgical or otherwise, or in an immunocompromised patient. Most life-threatening staph infections are acquired in a healthcare setting, such as a hospital or nursing home. Colonizing staph can cause serious conditions such as abscesses, osteomyelitis, staphylococcal pneumonia, septicemia, toxic shock syndrome and endocarditis.2 Around and in the eye, infection by Staphylococcus aureus can be the cause of preseptal and orbital cellulitis, lid abscess, conjunctivitis, corneal ulcers, endophthalmitis and blebitis.3

TREATMENT WITH ANTIBIOTICS

• MSSAStaphylococcus aureus was generally susceptible to the beta-lactam antibiotics when they were introduced in the early 1940s. Beta-lactams are the most widelyused group of antibiotics and they include penicillin, penicillin's synthetic derivatives (methicillin, oxacillin, nafcillin, cloxacillin, dicloxacillin and flucloxacillin) and the cephalosporins (cephalexin, cefadroxil, cefazolin, and others). Staphylococcus aureus microorganisms that demonstrate susceptibility to the antimicrobial effects of penicillin and its synthetic derivatives are referred to as methicillin-susceptible Staphylococcus aureus (MSSA).

• VSSA Vancomycin is a glycopeptide antibiotic that inhibits cell wall synthesis in Gram-positive bacteria.4Staphylococcus aureus microorganisms that are susceptible to vancomycin are referred to as vancomycin-susceptible Staphylococcus aureus (VSSA). Vancomycin is often effective in treating Gram-positive bacteria that are unresponsive to beta-lactams. Vancomycin will not pass across the gastrointestinal mucosa and therefore must be administered intravenously for systemic therapy, requiring in-patient care.4

DEVELOPMENT OF RESISTANCE TO ANTIBIOTICS

• MRSA In 1944, Staphylococcus aureus was found to demonstrate some resistance to penicillin, likely in response to the wide usage of beta-lactam drugs, making it the first known bacterium to acquire antibiotic resistance.5 Resistance to penicillin became widespread during the 1950s, and increasing resistance to the semisynthetic penicillinase-resistant antimicrobial agents (such as methicillin, oxacillin, nafcillin) followed in the 1960s.6

The resistance to these semisynthetic penicillins had become so prevalent by the 1990s that they could no longer be used as first-line empirical therapy for serious staphylococcal infections. Methicillin-resistant Staphylococcus aureus (MRSA) is the name given to Staphylococcus aureus microorganisms that have become resistant to penicillin and its synthetic derivatives.

• VRSA While vancomycin has been considered the drug of choice after treatment failure with other antibiotics, bacterial resistance to vancomycin has also developed during the past 20 years. Vancomycin-resistant Staphylococcus aureus (VRSA) is the name given to Staphylococcus aureus microorganisms that have become resistant to vancomycin.

TYPES OF MRSA

MRSA disease has become a major public health problem.7 Before the 1980s, MRSA was primarily considered to be a nosocomial infection — one that is acquired in a hospital or healthcare setting (such as nursing homes); not present or incubating prior to the patient being admitted to the health care facility, but occurring within 72 hours after admittance to the facility.8 Nosocomial MRSA infections are referred to as "Health Care-Associated Methicillin Resistant Staphylococcus aureus" (HA-MRSAa) infections to distinguish them from MRSA infections acquired in the general community outside of the healthcare setting.9,10 These staph infections occur most frequently among persons who have a weakened immune system7 and include surgical wound infections, urinary tract infections, bloodstream infections and pneumonia. Approximately 20% of bloodstream infections in the hospital setting are caused by S. aureus and the proportion of hospital-onset S. aureus infections that were methicillin-resistant reached 64.4% in U.S. intensive care units in 2003.7 Standardized mortality rate (in-hospital deaths) was 6.3 per 100,000.7

Approximately 1% of the population is colonized with MRSA.1 Klevens and colleagues7 reported that invasive MRSA infection is a major public health problem primarily related to health care but no longer confined to healthcare settings. Non-nosocomial MRSA infections are referred to as Community-Associated Methicillin Resistant Staphylococcus aureus (CA-MRSAb) infections. Individuals with these infections have neither been recently hospitalized (within the prior year) nor had a medical procedure (such as dialysis, surgery, catheterization). CA-MRSA infections typically manifest as skin infections such as pimples, abscesses and boils, and other pus-filled lesions.9,10

Since 1981, CA-MRSA has become the most frequent cause of skin and soft tissue infections presenting to emergency departments in the United States7,11 and the prevalence of CA-MRSA is rapidly increasing.5 Naseri and colleagues12 reported a significant increase in the prevalence of CA-MRSA head and neck infections in the pediatric population from 2001 through 2006. Blomquist3 reviewed the records of culture-positive MRSA patients in an urban public healthcare system (2000-2004) to identify patients with ocular, orbital and ocular adnexal infection. He found that the most common manifestation of ophthalmic MRSA infection was preseptal cellulitis and/or lid abscess, followed by conjunctivitis. Sight-threatening infections also occurred, including corneal ulcers, endophthalmitis, orbital cellulitis and blebitis.

The distinction between HA-MRSA and CA-MRSA is based upon genetic studies that show that isolates causing HA- and CA-MRSA infections are different species, meaning CA-MRSA organisms aren't HA-MRSA organisms that have simply moved into the general community.13 Differences in virulence factors between HA-MRSA and CA-MRSA organisms may allow the community strains to spread more easily or to cause more skin disease compared with the traditional hospital-based MRSA strains.1 HA-MRSA is typically a multidrug-resistant organism, while CA-MRSA isolates are usually susceptible to most nonbeta-lactam antimicrobial agents.13

TRANSMISSION AND CONTROL

Clinicians should be familiar with infection prevention control measures for clinical practice, must routinely use measures to prevent the transmission of MRSA, and know how to decrease the potential for MRSA infection through appropriate recommendations and patient counseling.

• HA-MRSA The most important reservoirs of MRSA in hospitals are infected or colonized patients. Hospital personnel are most commonly identified as the transmission link between patients, mainly via their hands, which may become contaminated by contact with colonized or infected patients, colonized or infected body sites of the personnel themselves, or from contact with devices, items or environmental surfaces contaminated with body fluids containing MRSA.14 HA-MRSA isolates can survive on a variety of inanimate surfaces, sometimes for weeks.15

Infection control is the key to limiting or eradicating MRSA and other health care-associated infectious pathogens in hospitals. Control measures include aggressive hand hygiene programs, interventions to reduce catheter-related bloodstream infections, ventilatorassociated pneumonia, and surgical site infections; and chlorhexidine bathing of ICU patients.16-19 Additional information on infection control in healthcare settings is available from the CDC.20

• CA-MRSA Factors known to increase the risk of spreading CA-MRSA skin and soft tissue infections include close skin-to-skin contact, openings in the skin such as cuts or abrasions, poor hygiene, crowded living conditions and contaminated items and surfaces.1 The presence of CA-MRSA isolates on items such as clothing, towels and athletic equipment may contribute to outbreaks. Settings, circumstances and activities that provide close contact conditions include households, schools, day care facilities, dormitories, military barracks, correctional facilities, athletics (particularly contact sports) and IV drug use. Groups in the population that tend to have a higher incidence of CA-MRSA infections include Native Americans, Pacific Islanders and men who have sex with men.15 CA-MRSA disease can even be shared between pets and human handlers, as demonstrated in cases where the pets (dogs, cats, livestock and birds) have been identified as the MRSA carriers.21,22

Advice for prevention of CA-MRSA transmission includes the consistent practice of appropriate personal hygiene, avoidance of an unclean/unsanitary environment and use of barriers to bacterial transmission.

Basic prevention advice for all individuals should include the following recommendations16,23:

■ Practice good personal hygiene:

– Keep hands clean by washing with soap and water regularly or by using an alcohol-based hand sanitizer. – Don't share personal items that come into direct contact with bare skin, such as towels and razors. – Avoid contact with other people's wounds or bandages. – Keep skin abrasions and cuts covered to prevent them from becoming infected (always use clean, dry bandages until healed).

■ Keep high-touch surfaces clean:

– High-touch surfaces (that are frequently in contact with hands) should be kept clean, and all surfaces that might come into direct contact with people's skin should be cleaned routinely.

■ Practice healthy hygiene in exercise and sports:

– Barrier-like clothing or a towel should be used between skin and equipment, such as weight-training benches. – Showering should be done immediately after participating in activities with frequent skin-to-skin contact, such as exercise and sports.

Basic infection control recommendations for clinicians includes using standard precautions24,25:

– after touching blood, body fluids, secretions, excretions and contaminated items, even when gloves are worn – between patients – when moving from a contaminated body site to a clean site on the same patient

■ Wear gloves when managing wounds

■ Wear gown and mask/eye protection or face shield for procedures that are likely to generate splashes or sprays of blood, body fluids, secretions or excretions

Additional information about CA-MRSA for both clinicians and the public is available from the CDC.10,26

INFECTION SURVEILLANCE PROGRAMS

The CDC plays a large role in MRSA surveillance by monitoring the incidence of health care-associated infections, the associated risk factors and pathogens by gathering data through the National Healthcare Safety Network (NHSN),27 a voluntary reporting system shared by all U.S. hospitals, long-term care facilities, other healthcare organizations and the CDC. The CDC also participates in MRSA prevention, epidemiologic and laboratory research, and outbreak and laboratory support.27

Another useful program is The Surveillance Network (TSN), which was established in 1994 as an electronic repository of infectious organisms, specimen sources and antimicrobial susceptibility data.28 TSN monitors the patterns of antimicrobial susceptibility of pathogens, such as MRSA, in infections requiring diagnostic testing. While most TSN data are from systemic infections, data from cultured ocular infections have also been captured, demonstrating an increase in the rate of ocular MRSA infections of 12.1% over a 5-year period (from 29.5% in 2000 to 41.6% in 2005) (Figure 1).28 Asbell and colleagues concluded that MRSA isolates soon may become the dominant phenotype in serious ocular S. aureus infections.28

TSN data also showed that MRSA in ocular infections could be classified as multidrug resistant, including all the fluoroquinolones tested, and that trimethoprim was the most effective agent against MRSA.28

Shortly after the TSN program was launched, the "Tracking Resistance in the U.S. Today" (TRUST) program was initiated in 1996 to assess pathogen susceptibility to fluoroquinolones and other antimicrobials when levofloxacin was first introduced for systemic use.29 The ongoing program allows for monitoring of trends in antibiotic resistance with nationwide susceptibility data. The TRUST program, however, did not systematically track in vitro susceptibility in ocular isolates. To fill this gap, Ocular TRUST began in 2005 as a longitudinal nationwide susceptibility surveillance program, tracking antimicrobial susceptibility patterns of common ocular pathogens. Ocular isolates are tested against a panel of antimicrobials representing six pharmacologic classes: fluoroquinolones (ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin); dihydrofolate reductase inhibitors (trimethoprim); macrolides (azithromycin); aminoglycosides (tobramycin); polypeptides (polymyxin B); and beta-lactams (penicillin).30 Among the results from the third year of Ocular TRUST31 (Figure 2):

■ Most antimicrobials, except penicillin and polymyxin B, continue to be highly active against MSSA (azithromycin shows only moderate activity).

■ With the exception of trimethoprim and tobramycin, less than one-third of MRSA strains are susceptible to ophthalmic antimicrobials.

■ Susceptibility profiles of the fluoroquinolones remain weak for MRSA.

TREATMENT OF MRSA

Clinicians should be aware of the currently recommended therapeutic regimens that incorporate new knowledge regarding the most effective antibiotics administered systemically or topically for both HA-MRSA and CA-MRSA.

• HA-MRSA Since HA-MRSA strains are multidrug-resistant organisms (MDRO), final therapy should be guided by results of susceptibility testing from cultures obtained before the initiation of empirical therapy.11,13,15,25 For initial empirical antibiotic therapy for HA-MRSA, Grayson25 has suggested vancomycin, linezolid, daptomycin or rifampin plus trimethoprim–sulfamethoxazole.

Treatment for severe infection (where the patient appears toxic, vital signs are unstable and a sepsissyndrome is present) would include the following:24

■ Intravenous therapy for MRSA is preferred; vancomycin remains a first-line therapy (although, owing to concerns about possible development of vancomycin-resistant bacteria, its use is restricted in most hospitals, and requires approval of the Infectious Disease Unit)4■ Final therapy based on results of culture and susceptibility testing■ Consult with infectious disease and critical care specialist

• CA-MRSA CA-MRSA infections often begin as skin or soft tissue lesions, such as a boil or abscess and/or cellulitis, with patients frequently reporting a lesion that is red, swollen and painful.24 CA-MRSA should be suspected particularly if a patient reports, or presents with, a wound resembling a spider bite, since MRSA strains can cause painful lesions in the absence of previous skin trauma.11

Moran and colleagues11 reported that while more than 80% of patients with skin and soft-tissue infections associated with MRSA received empirical antimicrobial therapy for their infections, 57% of those patients were infected with a MRSA isolate that was resistant to the agent prescribed. Susceptibility testing of MRSA isolates in this study revealed that 100% were susceptible to trimethoprim-sulfamethoxazole, 95% to clindamycin, 92% to tetracycline, and 60% to fluoroquinolones. Similar to their findings regarding susceptibility to trimethoprim-sulfamethoxazole, Asbell28 reported that trimethoprim is the most effective topically applied antibiotic against ocular MRSA infection.

In treating nonpurulent cellulitis, as in preseptal cellulitis, there is a chance that the infection involves group A streptococcus,31 which is mostly resistant to trimethoprim–sulfamethoxazole.11,15 For coverage of streptococcal infection, clindamycin or a combination of a beta-lactam plus trimethoprim–sulfamethoxazole may be preferable.11 Trimethoprim–sulfamethoxazole and tetracyclines are reasonable choices for cases where CA-MRSA infection is either confirmed or strongly suggested by the presence of purulent material.15

Asbell28 suggested that a clinician would be prudent to consider the possibility of methicillin or multidrug resistance with any Staphylococcus aureus ocular infection, even in the absence of recognized risk factors, because of recent increases in the prevalence of MRSA and the inability of clinical or epidemiological risk factors to reliably distinguish between CA-MRSA and MSSA.32 Ideally, cultures should be obtained for suspected MRSA infections, with the susceptibility profile of the organism(s) ultimately guiding the antibiotic treatment.11,24

Systemic antibiotics of interest in the treatment of S. aureus and MRSA infections

• Trimethoprim-sulfamethoxazole (co-trimoxazole), as a sulfonamide antibacterial combination, is effective against MRSA because it synergistically inhibits successive steps in the folate synthesis pathway, starving the bacteria of the folic acid that is necessary for DNA replication and transcription.• Clindamycin (a lincosamide antibiotic) can be effective against MRSA infections because it reduces the production of staph exotoxins and may also induce changes in the surface structure of bacteria that make them more sensitive to immune system attack (opsonization and phagocytosis).• Doxycycline, as a semi-synthetic tetracycline, is effective against MRSA infections primarily through inhibition of bacterial protein synthesis leading to bacteriostasis.• Daptomycin, a cyclic lipopeptide, acts on the bacterial cytoplasmic membrane and is bactericidal against most Gram-positive bacteria, including Staphylococcus aureus.• Linezolid, an oxazolidinone, is active against almost all CA-MRSA isolates and group A streptococci. High cost, lack of routine availability, hematologic side effects, and the potential for resistance among Staphylococcus aureus strains are relative contraindications for usage.• Rifampin is highly active against susceptible communityassociated MRSA isolates but it must be used in combination with trimethoprim-sulfamethoxazole or doxycycline due to high frequency of resistance when rifampin is used alone.• Fluoroquinolones interrupt bacterial replication by binding to both deoxyribonucleic acid (DNA) gyrase and topoisomerase IV. They should not be used to treat skin and soft-tissue infections caused by CA-MRSA since Staphylococcus aureus resistance develops readily and is already widely prevalent.• Augmentin (GlaxoSmithKline) — a combination of amoxicillin, a beta-lactam antibiotic, and clavulanic acid, a beta-lactamase inhibitor — addresses bacterial resistance to betalactam with the clavulanic acid antagonizing the beta-lactamase enzyme, binding irreversibly to it and allowing the amoxicillin to attack bacterial cell wall synthesis. Augmentin is effective in treating MSSA infection, but is not effective against MRSA.

The following is a treatment summary for initial empirical antibiotic therapy.

■ For MSSA, penicillinase-resistant penicillin or a firstgeneration cephalosporin should be used.25 (Note that the penicillins are more effective than vancomycin in treating MSSA.)■ For MRSA:• Generally: – avoid beta-lactam antibiotics (e.g., no penicillins or cephalosporins) for MRSA• Based on HA- or CA-MRSA:– HA-MRSA:-- Vancomycin25; alternatives to vancomycin, particularly to manage VRSA, include linezolid, daptomycin, trimethoprim, or rifampin plus trimethoprim–sulfamethoxazole.6,25,28 Asbell28 has reported that trimethoprim can be as effective as vancomycin in both systemic and ocular MRSA infections– CA-MRSA:-- Systemically:• trimethoprim–sulfamethoxazole, clindamycin, or a long-acting tetracycline such as doxycycline15,25• CA-MRSA can cause severe and sometimes fatal invasive disease.7,33 When a CA-MRSA infection is severe, it should be treated in the same manner as previously described for severe HA-MRSA infection.-- Ophthalmically:• while fluoroquinolones are commonly used to treat ocular surface infections, alternatives should be considered.29 Trimethoprim has been reported to be the most effective topically applied antibiotic that is active against MRSA.28-30

CONTROLLING MRSA

The increasing prevalence of MRSA has resulted in a paradigm shift to include this group of organisms in the differential diagnosis of numerous diseases, including those that affect the ocular tissues. The spread of MRSA can be controlled through appropriate steps by individuals, and clinicians must routinely use measures to prevent transmission of these organisms. To treat MRSA infection, clinicians should be aware of the currently recommended therapeutic regimens that incorporate new knowledge regarding the most effective systemic and topical antibiotics for HA-MRSA and CA-MRSA. CLS

Jimmy D. Barlett, OD, DOS, ScD Dr. Bartlett received his doctorate in optometry in 1974 from Southern College of Optometry. After serving as Chief of the Optometry Service at the Tampa V.A. Hospital and Assistant Professor in the Department of Ophthalmology of the University of South Florida College of Medicine, he assumed his present position at the School of Optometry, University of Alabama at Birmingham in 1977. Dr. Bartlett is Chairman of the Department of Optometry, Professor of Optometry in the School of Optometry and Professor of Pharmacology in the Department of Pharmacology and Toxicology at the University of Alabama School of Medicine. Dr. Bartlett has served as Editor-in-Chief of the Journal of the American Optometric Association, Co-editor of Clinical Ocular Pharmacology, and serves on the editorial advisory board for Ophthalmic Drug Facts and Journal of Ocular Pharmacology and Therapeutics. Dr. Bartlett has been engaged as a consultant and has been a member of the advisory boards of Alcon, Allergan, Bausch & Lomb and Vistakon.

Chris Snyder, OD, MS, FAAO Dr. Snyder earned a doctorate in optometry, a graduate degree and a residency certificate in contact lens practice from The Ohio State University. He served as an optometrist in the U.S. Navy and was a Professor of Optometry at the University of Alabama at Birmingham (UAB) School of Optometry for more than 24 years where he served as the Director and Chief of the Cornea and Contact Lens Service of UAB EyeCare and practiced optometry in the faculty practice. He has served as a Contributing Editor for Contact Lens Spectrum, as Co-editor of the International Contact Lens Clinic Journal and is the U.S. Regional Editor of the U.K.-based (British Contact Lens Association) indexed journal Contact Lens and Anterior Eye. Dr. Snyder is Director of Professional Relations for Bausch & Lomb U.S. Vision Care and continues an active relationship with UAB as an adjunct professor.